Chronic Use of Proton-Pump Inhibitors and Iron Status in Renal Transplant Recipients

Abstract

Proton-pump inhibitor (PPI) use may influence intestinal iron absorption. Low iron status and iron deficiency (ID) are frequent medical problems in renal transplant recipients (RTR). We hypothesized that chronic PPI use is associated with lower iron status and ID in RTR. Serum iron, ferritin, transferrin saturation (TSAT), and hemoglobin were measured in 646 stable outpatient RTR with a functioning allograft for ≥ 1 year from the “TransplantLines Food and Nutrition Biobank and Cohort Study” (NCT02811835). Median time since transplantation was 5.3 (1.8–12.0) years, mean age was 53 ± 13 years, and 56.2% used PPI. In multivariable linear regression analyses, PPI use was inversely associated with serum iron (β = −1.61, p = 0.001), natural log transformed serum ferritin (β = −0.31, p < 0.001), TSAT (β = −2.85, p = 0.001), and hemoglobin levels (β = −0.35, p = 0.007), independent of potential confounders. Moreover, PPI use was independently associated with increased risk of ID (Odds Ratio (OR): 1.57; 95% Confidence Interval (CI) 1.07–2.31, p = 0.02). Additionally, the odds ratio in RTR taking a high PPI dose as compared to RTR taking no PPIs (OR 2.30; 95% CI 1.46–3.62, p < 0.001) was higher than in RTR taking a low PPI dose (OR:1.78; 95% CI 1.21–2.62, p = 0.004). We demonstrated that PPI use is associated with lower iron status and ID, suggesting impaired intestinal absorption of iron. Moreover, we found a stronger association with ID in RTR taking high PPI dosages. Use of PPIs should, therefore, be considered as a modifiable cause of ID in RTR.

The association between use of proton-pump inhibitors and excess mortality after kidney transplantation: A cohort study

“…It has been widely documented that PPIs may affect absorption of micronutrients, leading to deficiencies of important electrolytes, including iron and magnesium PLOS MEDICINE [11,14,15]. Indeed, we previously found that PPI use was associated with iron deficiency and hypomagnesemia in KTRs [37,39]. Iron deficiency can in turn lead to iron deficiency anemia, which has been linked to a higher graft failure risk and mortality risk in KTRs [40][41][42].…”

“…To explore a potential dose-response relationship, we performed additional Cox regression analyses in which KTRs were divided into 3 groups based on daily PPI dose defined in omeprazole equivalents: no PPI, low PPI dose (�20 mg omeprazole equivalents/day), and high PPI dose (>20 mg omeprazole equivalents/day) as described previously [37]. Tests of linear trend were conducted by assigning the median of daily PPI dose equivalents in subgroups treated as a continuous variable.…”

Proton-Pump Inhibitors and Hypomagnesaemia in Kidney Transplant Recipients

“…PPI type and daily dosage were obtained from electronic patient records and are demonstrated in Table S1. KTR using any PPI on a daily basis during a period of at least 3 months prior to the study visit were defined as chronic PPI users as described previously [24]. To investigate a potential dose-response relationship, KTR were divided into three groups based on daily PPI dose defined in omeprazole equivalents: no PPI, low PPI dose (≤20 mg omeprazole equivalents/day (Eq/day)) and high PPI dose (>20 mg omeprazole Eq/day) [24,25].…”

“…Effect modification by loop diuretics, thiazide diuretics, tacrolimus and diabetes was tested by inclusion of interaction terms. To investigate a potential dose-response relationship we performed additional analyses in which KTR were divided into three groups based on daily PPI dose defined in omeprazole equivalents: No PPI, low PPI dose (≤20 mg omeprazole Eq/day) and high PPI dose (>20 mg omeprazole Eq/day) [24,25]. Tests of linear trend were conducted by assigning the median of daily PPI dose equivalents in subgroups treated as a continuous variable.…”

Choice of Acid Suppressant Therapy and Long‐Term Graft Outcomes After Kidney Transplantation

“…16,17 Other transplant studies have demonstrated associations between PPI use and hypomagnesemia, Clostridium difficile infections, iron deficiency anemia, and increased fracture risk. [18][19][20][21][22][23][24] However, these studies did not compare PPIs to H2RAs [18][19][20][21][22] and included relatively small cohorts. 23,24 Most studies comparing the impact of PPI or H2RA use on renal function posttransplant report outcomes up to a year posttransplant.…”